Role of histotripsy synergized CD40 signaling in the re-engineering of cold tumors

项目摘要 晚期转移性黑色素瘤是皮肤癌中最致命的一种，通常对化疗和化疗有抵抗力。 放疗对于这些患者来说，免疫检查点抑制剂（ICI）的出现是一场革命。 改变，提高肿瘤缓解率和生存率，逆转先前缺乏进展。尽管前景看好， 大部分患者，特别是那些免疫原性差（“冷”）肿瘤的患者，仅表现出适度的免疫原性， 对ICI的反应，甚至反应者经常复发。新的肿瘤再造技术迫切需要 需要提高免疫抵抗性冷肿瘤患者的生存率。该项目的目标是 优化基于局部聚焦超声的组织摧毁术（HT）和抗 CD 40激动剂抗体（aCD 40）包封的聚合物微粒（CMP）以重编程冷黑素瘤 肿瘤的HT在实体癌中无创且快速地产生具有尖锐边界的无细胞抗原库， 而aCD 40激活抗原呈递细胞（APC）。我们的小鼠黑色素瘤研究发现，CMP比 与单独的可溶性aCD 40相比是有效的，并且当与ICI/HT组合时， 未经治疗的肿瘤基于这一前提，我们将检验肿瘤内给药的中心假设， 具有肿瘤抗原捕获和HT持续活化CD 40双重功能的CMP将实现 持久缓解局部治疗和远程未治疗的黑色素瘤。为了验证我们的假设，目的是 1)确定HT和CMP联合方案在免疫原性不同的小鼠肿瘤模型中的疗效 和负担，2）阐明了用HT和CMP驱动远位效应的ICI抗性逆转机制， 和3）将我们的发现转化为患有自发性恶性黑色素瘤的狗兽医患者的临床试验。 狗黑色素瘤类似于人黑色素瘤，并且侵袭性转移，并且有利于治疗。 评估我们的组合疗法的可翻译性将免疫学上的“冷”肿瘤转化为 在晚期癌症中使用免疫原性药物是一个具有挑战性的目标。项目成果将使快速 通过局部产生可与CD 40协同作用的大肿瘤抗原库激活冷黑色素瘤 信号传导以改善对局部治疗和远处未治疗的肿瘤的功效。我们的临床研究- 相关模型将告知改善大部分转移性黑色素瘤患者生存率的可行性 对免疫疗法有抵抗力的肿瘤。

Project Summary Advanced-stage metastatic melanoma is the deadliest form of skin cancer, typically resistant to chemo- and radiotherapy. For such patients, the advent of immune checkpoint inhibitors (ICIs) has been a revolutionary change, improving tumor remission and survival rates, reversing prior lack of progress. Although promising, a large proportion of patients, especially those with poorly immunogenic ("cold") tumors, show only modest response to ICIs, and even responders relapse frequently. New tumor-reengineering technologies are urgently needed to improve survival rates in patients with immunoresistant cold tumors. The objective of this project is to optimize an innovative combinatorial therapy based on local focused ultrasound-based histotripsy (HT) and anti- CD40 agonist antibody (aCD40) encapsulated polymeric microparticles (CMPs) to reprogram cold melanoma tumors. HT non-invasively and rapidly generates acellular antigen depots with sharp boundaries in solid cancers, while aCD40 activates antigen-presenting cells (APCs). Our murine melanoma studies found that CMP is more efficacious compared to soluble aCD40 alone, and when combined with ICI/HT achieves complete remission of untreated tumors. Based on this premise, we will test the central hypothesis that intratumorally-administered CMPs that serve the dual functions of tumor antigen capture and sustained CD40 activation with HT will achieve durable remission of locally-treated and remote untreated melanomas. To test our hypothesis, the aims are to 1) Determine efficacy of the HT and CMP combined regimen in murine tumor models varying in immunogenicity and burden, 2) Elucidate ICI resistance reversal mechanisms that drives abscopal effects with HT and CMP, and 3) translate our findings to clinical trials in dog veterinary patients with spontaneous malignant melanoma. Dog melanoma resembles human melanoma, and metastasizes aggressively, and is advantageous for assessing translatability of our combinatorial therapy. Transforming immunologically “cold” tumors to immunogenic ones in advanced stages of cancer is a challenging goal. The project results will enable rapid activation of cold melanomas by locally generating large tumor antigen depots that can synergize with CD40 signaling to improve efficacy against locally treated and distant untreated tumors. Our studies in clinically- relevant models will inform feasibility of improving survival in a large proportion of metastatic melanoma patients with immunotherapy-resistant tumors.